Tuberculosis (TB) and Human immunodeficiency virus (HIV) cooperate to drive a deadly co-epidemic that results in approximately 12 million new infections and 4.5 million deaths annually. TB is the leading cause of death in people living with HIV infection, and the risk for new Mycobacterium tuberculosis (Mtb) infections and TB relapse continue despite restoration of T cells by anti-retroviral (ARV) therapy. A spectrum of immune dysfunction in human subjects with dual disease is well described, including both immune suppression and inappropriate inflammation. The mechanistic bases for many of these outcomes of co-infected individuals, however, are poorly understood and represent an important gap for development of host directed interventions to: 1) restore protective immune responses, 2) reduce pulmonary damage, and 3) complement standard drug therapy. We exploited our access to relevant human tissues and biologicals, and utilized our humanized mouse co-infection model, to identify novel candidate mechanisms for co-infection pathophysiology. As a result, we have preliminary data supporting an HIV-mediated effect to compromise the function of an immune-regulatory C-type lectin receptor in lung macrophages (M?). The objective of this R01 application is to identify HIV-mediated defects in human M? due to native and experimental infection, and demonstrate the impact of these defects in the setting of pulmonary TB. Our hypothesis is that that HIV modulates immunoregulatory CLRs in pulmonary M? and compromises an important innate signaling pathway for recognition and resolution of tissue damaging inflammation in Mtb-infected lungs. We propose the following two aims to test this hypothesis: 1) Determine how compromise of immunoregulatory CLR pathways by HIV promotes pulmonary inflammation following Mtb infection, and 2) Identify mechanism(s) whereby HIV compromises CLR pathways as therapeutic targets to reduce inflammatory outcomes in Mtb/HIV co-infected lungs. These aims will be accomplished by using bio- banked biologicals and tissue from HIV+ donors, in vitro systems, gene deficient mice, and humanized mice. We are well positioned to carry out these studies as our interdisciplinary TB/HIV co-infection team includes immunology, pathology, molecular biology, animal model, and medicinal chemistry expertise. In phase I, we propose to demonstrate that HIV infection interferes with the anti-inflammatory function of MGL and demonstrate the consequences of MGL dysfunction in the Mtb-infected lung. In phase II, we will establish the mechanisms for HIV-mediated disturbance of MGL and explore novel CLR pathway targets as potential therapeutic approaches to reduce pulmonary damage in the setting of TB.